Predicting Bile and Lipid Interaction for Drug Substances

Abstract

Predicting biopharmaceutical characteristics and food effects for drug substances may substantially leverage rational formulation outcomes. We established a bile and lipid interaction prediction model for new drug substances and further explored the model for the prediction of bile-related food effects. One hundred and forty-one drugs were categorized as bile and/or lipid interacting and noninteracting drugs using 1H nuclear magnetic resonance (NMR) spectroscopy. Quantitative structure–property relationship modeling with molecular descriptors was applied to predict a drug’s interaction with bile and/or lipids. Bile interaction, for example, was indicated by two descriptors characterizing polarity and lipophilicity with a high balanced accuracy of 0.8. Furthermore, the predicted bile interaction correlated with a positive food effect. Reliable prediction of drug substance interaction with lipids required four molecular descriptors with a balanced accuracy of 0.7. These described a drug’s shape, lipophilicity, aromaticity, and hydrogen bond acceptor capability. In conclusion, reliable models might be found through drug libraries characterized for bile interaction by NMR. Furthermore, there is potential for predicting bile-related positive food effects.

Structural Investigation on How Guest Loading of Poly(2-oxazoline)-Based Micelles Affects the Interaction with Simulated Intestinal Fluids

“…In combination, the increased solubility and contacts between Cur and TC strongly suggest a major contribution of TC for solubilizing Cur in FeSSIF. Considering the solubility and interactions of EFV with FeSSIF, this suggests that the ability of FeSSIF to dissolve drugs is dependent on a variety of molecular properties determining the nature of aggregation with FeSSIF, which is in good agreement with recent work on a bile and lipid interaction prediction model for new drug substances by Schlauersbach et al 69 In order to get a more detailed understanding Cur and TC aggregation, quantum chemical calculations of homo-and heterodimers were performed.…”

Bile Is a Selective Elevator for Mucosal Mechanics and Transport

“…We recently linked bile interaction to the chemical structures of drugs . Two descriptors were sufficient, lipophilicity (the previous study used h_logD and is now replaced by the logD at pH 7.4) and the molecular size and polarizability (CrippenMR). − The results were used to train an algorithm, which is now open-access ().…”

“…B ile s alt m icelles ( BSMs ) critically impact the absorption of fat, dietary components, and pharmaceuticals. − These colloidal structures consist of l ecithin ( L ) and bile acids, such as t auro c holate ( TC ). − BSMs, including solubilized molecules, shuttle from the intestinal lumen through the mucus layer to the intestinal epithelial surfaces. , Hydrophobic and positively charged molecules have limited mucus permeability and bioavailability. − Recent studies linked mucus binding to structural motifs of molecules, providing a starting point to study the hypothesis of bile effects on the molecule–mucus interplay …”

Molecular Dynamics Simulations of Self-Assembling Colloids in Fed-State Human Intestinal Fluids and Their Solubilization of Lipophilic Drugs

“…The results in Figures 7 and 8 can be compared to a recent study by Schlauersbach et al, 44 who introduced a solubility prediction tool based on descriptors and H-NMR shifts representative of interactions with either bile components (taurocholate and phospholipids) or lipids (monoglycerides). In this study, prednisolone was classified as bile interacting and nonlipid interacting, whereas fenofibrate was classified as both bile and lipid interacting.…”